Nonobese diabetic (NOD) mice spontaneously develop Type one diabetes (TID) and are a well established model of a complex polygenic genetically controlled autoimmune disease. Genome scanning has established at least 20 Insulin dependent diabetes (Idd) loci in the NOD mouse, and congenic mice have been constructed which are NOD mice except for B6/B10 genetic intervals containing Idd loci which prevent/reduce diabetes incidence. However it is not yet known how the Idd loci act to prevent diabetes. T cells play a major role in T1D pathogenesis. We have used a set of NOD congenic mice to demonstrate that NOD CD4+ T cells have a dysregulated, intrinsic, genetically controlled cytokine effector profile skewed towards an excessive Th1 response. We propose that a subset of Idd loci act to disrupt tolerogenic mechanisms and skew the Th1/Th2 cytokine balance in NOD CD4+ T cells. The NOD CD4+ T cells are prime mediators of loss of self-tolerance and are primary targets for therapeutic efforts aimed at restoring self-tolerance. Although T1D in NOD can be prevented by a large number of immune and non-immune interventions, only one approach has been demonstrated to reverse established hyperglycemia, i.e. infusion of anti-CD3 antibody. Anti-CD3 therapy has also reversed acute rejection, autoimmune arthritis and a variety of other inflammatory conditions. In addition it has recently been demonstrated to benefit new onset T1D in humans as well. The mechanisms by which anti-CD3 reverses autoimmune disease are still unclear. However, our own data as well as a large body of evidence identifies T cells diverted to a Th1 cytokine effector phenotype as central to TID pathogenesis and suggests our hypothesis, that anti-CD3 acts therapeutically by restoring a tolerogenic cytokine response in NOD CD4+ T cells. This grant combines immunogenetic, molecular and cellular approaches to dissect genetic control of T cell function in NOD mice and mechanisms of anti-CD3 therapy in T1D. The Co-P.l.s have extensive experience with NOD T cells, anti-CD3 therapy and mechanisms, and molecular dissection of APC function and present a cross-disciplinary approach to dissect mechanisms of T1D pathogenesis and immunotherapy.